Nonlinear feedback drives homeostatic plasticity in H2O2 stress response

Homeostatic systems that rely on genetic regulatory networks are intrinsically limited by the transcriptional response time, which may restrict a cell’s ability to adapt to unanticipated environmental  challenges. To bypass this limitation, cells have evolved mechanisms whereby exposure to mild stress   increases tolerance to subsequent threats. However, the mechanisms responsible for such adaptive homeostasis remain unknown. Here, we used live-cell imaging and microfluidics to investigate the  adaptive response of budding yeast to temporally controlled H2O2 stress patterns. We demonstrate  that acquisition of tolerance is a systems-level property resulting from nonlinearity of H2O2 scavenging by peroxiredoxins, and that this regulatory scheme drives a direct hormetic effect of H2O2 on replicative longevity. Our study thus provides a novel quantitative framework bridging the molecular architecture of a cellular homeostatic system to the emergence of nonintuitive adaptive properties.